HAART is not reducing risk of anal cancer in gay men

A study of HIV-positive gay men in San Francisco has found that 95% have anal HPV (human papilloma virus) infection, and more than 50% have grade 2 or 3 anal intraepithelial neoplasia (AIN), precursors of anal cancer. The study, which appears in the September 2^nd edition of AIDS, confirms other studies which suggest that highly active antiretroviral therapy (HAART) is not protective of AIN, and found that the men on HAART actually had an increased risk of AIN. Although the study does not suggest that HAART itself increases the risk of AIN, it does, at the very least, support the conclusion that HAART does not reduce the risk, and that the prevalence of anal cancer amongst HIV-positive gay men on HAART continues to increase.

Dr Joel Palefsky and colleagues from the University of California, San Francisco (UCSF), have published extensively on the incidence and treatment of HPV infection, AIN and anal cancer in HIV-positive gay men. Their latest study sought to determine the factors associated with, and prevalence of, AIN in a cohort of HIV-positive gay men, and to determine whether HAART use was associated with lower prevalence.

Gay men were recruited into this cohort study through newspaper advertisements and community outreach at the UCSF between February 1998 and January 2000. A total of 357 HIV-positive gay men were enrolled, and stratified according to their current antiretroviral regimen: no antiretrovirals (n=50, 14%), non-HAART regimen (n=40, 11%) and HAART regimen (n=267, 75%), the latter of which was defined as three or more antiretrovirals including at least one protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). There were no significant differences in baseline characteristics apart from the mean age of men using a non-HAART regimen which was, at 44, three years higher than the men not on antiretrovirals (age = 41, p<0.05).

Only 25 (7%) had never taken any antiretroviral regimen, and most had used between two and five nucleoside reverse transcriptase inhibitors (NRTIs) in their lifetime, although 8% had used between six and ten; 36% had ever taken at least one NNRTI; and whilst 31% had only ever taken one PI, 15% had taken four or five PIs. Lamivudine (3TC, Epivir; 59%) was the most commonly used, currently taken antiretroviral, followed by stavudine (d4T, Zerit; 52%), indinavir (Crixivan 26%) and zidovudine (AZT, Retrovir; 25%). In total, 137 different antiretroviral combinations were currently being used.

All the men were tested for CD4 cell counts and viral load. They also answered extensive lifestyle and medical history questioning, and underwent clinical examination. PCR testing defined 26 different HPV types; anal cytology via PAP smears were classified as normal, atypical squamous cells of undermined significance (ASCUS), AIN 1, 2 or 3; and anal biopsies were classified as normal, atypical, AIN 1, 2 or 3. The more serious of either the cytology or biopsy results were used (the higher the number the more serious the risk of anal cancer), unless the biopsy proved to be normal, in which case the result was considered indeterminate and the data excluded from analysis.

AIN & CD4 cell counts and viral load

The researchers found no significant association between CD4 cell count or viral load and AIN. AIN of any grade was found in 81% of the men with available CD4 cell counts: 29% had AIN 1 or condyloma; 39% had AIN 2 and 13% had AIN 3. There was a non-significant trend towards an increased risk of AIN with decreasing CD4 cell counts (p<0.07), and there was no association between AIN and viral load.

In comparison, a recent four city US study found a 20% prevalence of anal cancer precursor cells in 1262 HIV-negative gay men (Chin-Hong 2005).

AIN & HPV infection

As expected from previous studies, the researchers found a significant association between HPV and AIN. Of the 354 men with an anal swab available for HPV testing, 31 (8.8%) tested negative for beta-globulin resulting in 323 evaluable men. Of these, 308 (95%) had anal HPV infection. The men with anal HPV infection had a 15-fold increased risk (95% CI 4.0-57) of AIN of any stage and a 19-fold increased risk (95% CI 3.7-101) of AIN 2 or 3, compared with HPV-negative men. The investigators also found a statistically significant trend (all p<0.001) for the risk of AIN with increasing number of HPV types. Of the 128 men with six or more HPV types, 120 (94%) had any AIN, and 85 (66%) had AIN 2 or 3. Conversely, among the 163 men diagnosed with AIN 2 or 3, HPV was detected in 160 (98%).

AIN & HAART

The researchers found that the men who were taking antiretrovirals had an increased risk for any grade of AIN (OR 6.1; 95% CI, 2.6-14), and of AIN 2 or 3 (OR 6.3; 95% CI, 2.5-16), compared with those men who were not taking antiretrovirals. Although the men on HAART had an equivalent risk of any grade of AIN (OR 6.0; 95% CI, 2.5-14 vs. 6.1; 95% CI, 1.4-26) to those men taking antiretroviral therapy not classed as HAART, the risk of AIN 2 or 3 was higher for the men on HAART (OR 6.3, 95% CI 2.5-16) compared with the men taking a non-HAART regimen (OR 5.2; 95% CI, 1.0-26; p<0.001). The risks for any AIN, or AIN 2 or 3, also increased significantly with increasing time on HAART (p<0.001), and the number of antiretroviral drugs ever used (p<0.001).

AIN & other risk factors

Men who had a history of PCP, oral or oesophageal Candidiasis, shingles, Molluscum contagiosum or aciclovir use (as a marker of herpes infection) also had an increased risk of any AIN or AIN 2 or 3, even when adjusted for CD4 cell count. However, the researchers found that that was no association between any grade of AIN, or AIN 2 or 3, and race, education, time since HIV diagnosis, changes of medications in the past three years, drug holidays, antiretroviral adherence, time on current regimen, sexual activities, use of alcohol, tobacco, or recreational drugs, or other medical conditions or therapeutic drugs.

HPV & HAART use increases AIN risk

When a model that included the number of HPV types, CD4 cell count, HIV viral load and current viral load was adjusted for length of time since HIV-positive diagnosis, CD4 cell count and HIV viral, both the number of HPV types and current use of HAART were associated with an increased risk of any AIN or AIN 2 or 3. Having six or more HPV types increased the risk of any AIN 36-fold (95% CI, 7.4-171) and AIN 2 or 3, 108-fold (95% CI, 15-763) compared with no HPV infection. The men currently taking HAART had a 10-fold increased risk (95% CI, 2.6-38) of any AIN and a 12-fold increased risk (95% CI, 2.4-64) compared with the men not currently taking antiretrovirals.

"At a minimum HAART does not reduce the risk of AIN"

The investigators write that although their findings suggest that HAART appears to increase the risk of AIN, they "do not suggest that use of HAART directly increases the risk of AIN," but rather, "at a minimum they do support the conclusion that HAART use does not reduce the risk for AIN." They explain their findings by suggesting that the "men on HAART are different from those not on HAART in several ways and it is possible that the increased risk for AIN in this study reflected unmeasured differences between the two groups." This might include lifetime cumulative immunosuppression, a risk factor which is suggested by the association between an increased risk of AIN and "lifetime usage of antiretrovirals, history of pneumocystic and candidiasis, and the total number of different antiretroviral drugs ever used."

A role for earlier HAART?

The authors discuss the idea, supported by pre-HAART AIN studies, that immune suppression may be more important early in the natural history of AIN, but that other factors, including chromosomal changes, may be more important when it comes to the persistence of high-grade AIN and progression to cancer. They hypothesise that earlier use of HAART at higher CD4 cell counts than current treatment guidelines recommend may affect the natural history of AIN, but this would be difficult to prove unless studies were set up to specifically examine this issue. Nevertheless, they suggest that a possible benefit of HAART has been seen once cervical intraepithelial neoplasia has been treated in HIV-positive women, and so the relationship between HAART use and response to treatment for AIN should also be the subject of further investigation.

More studies "urgently needed"

The investigators conclude by stating that "unlike most other HIV-related malignancies, the incidence of anal cancer has been increasing since the introduction of HAART. Studies to document the utility of treatment of AIN 2 or 3 to prevent anal cancer are urgently needed."